Wound care compositions

ABSTRACT

Compositions for the treatment of wounds and skin injuries are described. The compositions, which include gellan gum, increases in viscosity once applied to the wound to form an immobile gel. The composition may be in sprayable form or dispersed in an aqueous solution. Methods of making and using the compositions are also described.

This application claims the benefit of priority of United Kingdom PatentApplication No. GB 0015682.8, filed on Jun. 28, 2000, the entirecontents of which are herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compositions for the treatment of wounds orother skin injury.

BACKGROUND OF THE INVENTION

A variety of gels and ointments are available for application to woundsfor a variety of purposes. They may, for example, be used to clean awound, to promote healing of the wound or to prevent infection. Incertain circumstances, the gel or ointment may include an activeingredient which is administered to the patient by topical applicationof the gel or ointment.

One example of a commercially available wound gel is Intrasite® producedby Smith and Nephew Ltd. This gel contains hydrated carboxymethylcellulose as a main ingredient and is packaged and applied to wounds ingel form as a primary treatment in order to debride the wound. The gelmay also assist in preventing the wound from drying out, therebypromoting healing.

Wound gels are generally in gel form at the time of application to thewound and are usually applied by being squeezed from a tube or othersuitable container by hand or by other suitable means. Since gels aremobile they offer the advantage of intimate contact with the oftenirregular surface of a wound, something that is often not achieved witha more rigid wound dressing. The advantage of good contact is howevertempered by the conflicting needs of making the gel sufficiently mobilethat it can be applied to the wound but not so mobile that it runs outof the wound under the influence of gravity. Gels currently in usesuffer from the disadvantage that they can run out of the wound. Thus,there is a need in the art for a composition for topical application toa wound which forms an immobile gel when in contact with the wound orskin injury.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a parallel plate used in measuring viscosity.

SUMMARY OF THE INVENTION

The present invention is directed to a composition for the treatment ofa wound or skin injury. The inventive composition comprises between0.25% to 1.5% by weight of the composition of a gellan gum. In preferredembodiments, the composition can comprise from 0.5% to 1.0% of gellangum by weight of the composition.

The viscosity of the composition increases once applied to a wound sothat an immobile gel is formed. Prior to application to the wound, thecomposition can be in sprayable form and/or in a spray device which, onactuation, discharges a metered dose of the composition. The compositioncan also comprise an active ingredient dissolved or dispersed in thecomposition. The active ingredient can be dissolved or dispersed in anaqueous solution of gellan gum. In preferred embodiments, the activeingredient is selected from the group consisting of hyaluronic acid,esterified hyaluronic acid, an antiseptic, an antifugal agent, anantibacterial agent, and mixtures thereof. In some embodiments, theactive ingredient is present in an amount of 0.1 to 10% by weight of thecomposition.

Preferably, the viscosity of the inventive composition is between 0.1 to12 Pas, prior to application to the wound. Also preferably, thecomposition develops a viscosity of from 13 Pas to 800 Pas once incontact with the wound.

Also included in the present invention are methods for treating woundsusing the inventive composition.

Still further included in the present invention is an apparatus forforming an immobile gel dressing on wound or skin injury, the apparatuscomprising a composition comprising from 0.25% to 1.5% by weight of thecomposition of a gellan gum, a vessel containing the composition, and adispensing means in fluid connection with the composition so that thecomposition can be applied to the wound or skin injury.

Yet still further included in the present invention are methods offorming an in situ immobile gel on a wound or skin injury. These methodscomprise dispensing an effective amount of a composition on the wound orskin injury, so that the viscosity of the composition increases andforms an immobile gel. In preferred methods, the composition is 0.25% to1.5% gellan gum as measured by weight of the composition. In someembodiments, the method includes a dispensing step which comprisesspraying, painting or squirting the composition on the wound or skininjury.

DETAILED DESCRIPTION OF THE INVENTION

We have found that it is possible to make a composition for topicalapplication to a wound which forms an immobile gel once in contact withthe wound or skin injury.

Accordingly, the invention provides a composition for the treatment of awound or skin injury comprising from 0.25% to 1.5% by weight of thecomposition of a gellan gum, said composition forming an immobile gelonce in contact with the wound or skin injury.

This gives the advantage that the composition can be applied in a mobilestate to give intimate contact with the wound but forms an immobile gelonce in contact with the wound reducing the tendency for the gel to runout of the wound. Such a composition is particularly suitable foradministering active ingredients to a wound.

Preferable the composition is in sprayable form prior to application tothe wound. This offers ease of application of the composition which onceapplied to the wound forms an adherent cohesive mass.

The composition may be a solution in water or a mixture of watertogether with another water-miscible solvent, such as propylene glycol.

By the term, “gellan gum” as used herein, is meant the extracullarlyproduced gum made by processes well known in the art. Gellan gum iscomposed of sugar monomer units linked together to form long chains ofthe individual sugar or monosaccharide units. Particularly preferred isgellan gum described in Carbohydrate Polymers, Vol. 30, 1996: SPECIALISSUE, GELLAN GUM: STRUCTURES, PROPERTIES AND FUNCTIONS. Ed. NishinariK., Pub. Elsevier Science 1996 and “Physicochemical properties of Gellangum in gel and solution.” Author Tsiami Amalia A. Pub. University ofEast Anglia 1994.

While not wishing to be bound by theory it is believed that gellan gumforms a gel once applied to a wound because molecular association of thesaccharide repeat units is promoted due to exposure of the gum tocations contained in the wound and wound exudate.

While many polysaccharides form gel structures it tends to be underspecific circumstances, for example the gelation of Carrageenas issensitive to the ion type e.g. gelling with potassium but not sodium.Glycuronans e.g. alginate gel in the presence of divalent cations butnot monovalent cations. Xanthan gum will gel with divalent cations butonly at high pH's. Pectic materials gel on cooling if completelyesterified or in the presence of divalent cations if incompletelyesterified. However Gellan gum is not specific and forms a gel withalmost all cations. Suprisingly we have found that gellan gum gels atthe relatively low ion concentrations found in a wound environment incontrast to other polysaccharides.

The composition preferably comprises an active ingredient. The term“active ingredient” is used herein to refer to any agent which affectsthe metabolism or any metabolic or cellular process of the patient(including growth factor nutrients and living cells), promotes cleaningof the wound, combats infection, hypergranulation, inflammation and/oraids in healing. One advantage of delivering the active ingredient inthis way is that gellan gums may provide controlled release of activeingredients.

Active ingredients may include other polysaccharides such as hyaluronicacid, salts of hyaluronic acid, esters of hyaluronic acid andhydrocolloids such as sodium carboxymethyl cellulose, pectin andalginate, antiseptic agents such as povidone iodine, antifungal agentssuch nystatin and Econazole nitrate and antibaterial agents aspolymyxin, metronidazole and silver sulphadiazine.

For administration to a patient the composition of the invention may beplaced in an apparatus. In a further aspect the invention provides anapparatus for forming an immobile gel dressing on a wound or skininjury, the apparatus comprising:

a) a composition comprising from 0.25% to 1.5% by weight of thecomposition of a gellan gum;

b) a vessel containing the composition; and

c) a dispensing means in fluid connection with the composition so thatthe composition can be applied to the wound or skin injury.

The apparatus may be adapted to spray the composition and may be acontainer fitted with a mechanical pump or a container pressurized witha propellant, for example a conventional aerosol propellant such asnitrogen or a hydrocarbon. The spray device preferably discharges ametered dose of the composition on actuation. In general the metereddose may be up to 0.2 g per actuation.

The composition prior to application to a wound preferably has aviscosity of between 0.1 Pas 12 Pas as measured by a Carrimed CSL 100Rheometer at 35.5° C. and 1Hz.

Compositions with these viscosities have been found particularlysuitable for application by spraying. Once delivered to the wound thecomposition develops into a gel that has a viscosity typically of from13 Pas to 800 Pas after a period of from 0.5 to 40 minutes.

The invention is illustrated by the following Examples in which partsare by weight.

EXAMPLES

Sprayable gel compositions for the treatment of wounds were prepared bymixing gellan gum (Kelcogel F low acyl content ex Kelco Nutrasweet) withpropylene glycol, buffered to pH 7 using a phosphate buffer solution asdescribed in the US Pharmacopoeia 1990 (9% by weight of total weight ofgel), water and sodium hyaluronate to yield the following compositions.

Composition/% w/w Example Gellan Propylene Buffer Sodium No. Gum GlycolpH 7.0 Water Hyaluronate 1 0.80 15 9 75.10 0.1 2 0.80 15 9 74.70 0.5

The time to gel onset and viscosity of the compositions was measuredusing a rheometer. A sample of the composition is injected on to a padsoaked in 0.9% w/w saline placed on the bottom plate of a parallel pair(see FIG. 1.). A sufficient volume of sample is injected into the spacebetween the plates so as to be in contact with the top plate and thesaline soaked pad. During the experiment the force required to rotatethe top plate of the pair by a small angle is measured. The movement ofthe top plate is in the form of a small amplitude oscillation.

When the distance moved by the plate and the force required to oscillatethe plate are plotted, the two curves are displaced from each other.This displacement may be measured in degrees and is termed the phaseangle. For an ideal liquid this angle is 90° and for a solid it is 0°and for most real materials it is somewhere between the two extremevalues. During the gelation process for the gellan materials this phaseangle is observed to rapidly fall and then the rate of change reduces.This is associated with an increase in viscosity and is taken as thetime at which the gelation starts for these examples. As the solutionbecomes less able to flow the phase angle falls and the material startsto behave as a conventional solid. This process continues for aconsiderable time after the onset of gelation, as the system approachesits new equilibrium conformation. The time taken for the gel onset tooccur, the viscosity of the solution and the stiffness of the final gelare dependent on the concentrations of the ions present and their type(sodium, potassium, calcium etc.), temperature, and the composition ofthe gel solution.

The follwing parameters were set.

Plate diameter and type 4 cm diameter acrylic Plate spacing 2.500 mmTest frequency 1 Hz Temperature 35.5° C. Controlled variableDisplacement Applied amplitude 1.250 × 10−3 rad. Pad Paper 68 to 72 gsmPad size 5 cm by 5 cm Pad fluid handling 8 g per g to 9 g per g

The sample to be tested was heated in a water batch to 35.5° C. A 5 cmby 5 cm minimum square of the pad material was soaked in 0.9% saline andplaced on the lower heated platen of the rheometer and readings started.

After the first two data points have been established the sample to betested is injected into the gap between the top plate of the rheometerand the pad. This is the initial time point of the experiment. Theexperiment is allowed to continue for 45 minutes.

Gel onset is the first point of inflection after the sample wasintroduced in the phase angle/time plot. The results were as follows:

Viscosity of the compositions as they cure.

TABLE 1 Viscosity data for example 1 Viscosity/Pa · s Time to gel At gelIncrease Viscosity of gel/Pa · s Example 1 onset/s Initial onset %Initial 5 min 10 min 15 min 20 min 40 min 15 3.23  4.22 31 3   11   95  313   375   738   55 4.38  6.25 43 4   15   142   395   581   962   598.13 10.63 31 8   17   112   268   408   794   Average 43 5.3  7.0 355.00 13.00 116.33 325.33 454.67 831.05 St dev 24 2.6  3.3  7 2.65  2.83 23.80  64.39 110.65 116.37

TABLE 2 Viscosity data for example 2 Viscosity/Pa · s Time to gel At gelIncrease Viscosity of gel/Pa · s Example 1 onset/s Initial onset %Initial 5 min 10 min 15 min 20 min 40 min 47  8.1 11.2 38 8   19   92  144   165   340   63 12.0 16.7 39 12   22   78   113   145   291   6515.6 20.6 32 16   31   101    145   196   391   Average 58 11.9 16.2 3712.00 20.50 90.33 134.00 153.50 340.67 St dev 10  3.8  4.7  4  4.00 2.12 11.59 18.19  12.02  50.00

The initial gelation process is the start of a chain of events whichchanges the gel solution from a liquid to a solid. This change of stateresults in a change of the phase angle measured for the gel. The phaseangle reduces as the solution solidifies. This solidification isassociated with an increase in the measured viscosity. The results inTables 1 & 2 show for examples 1 & 2 (Tables 1 & 2) that although theinitial solution viscosities are different, there are similar percentagechanges in the two solutions as the initial gelation occurs (35%+/−7%for example 1 and 37%+/−4% for example 2). The data in the tables thatrelate viscosity to time show that the gelation process continues formany minutes after the initial gel onset, resulting in a 166 foldincrease in the viscosity of example 1 and a 28 fold increase in example2 after 40 minutes.

TABLE 3 Shear modulus data for example 1 Viscosity/Pa · s Time to gel Atgel Increase Shear modulus/Pa Example 1 onset/s Initial onset % Initial5 min 10 min 15 min 20 min 15 3.23  4.22 31 37 75   671 2012 2385 554.38  6.25 43 44 87   957 2522 3652 59 8.13 10.63 31 56 93   708 17142534 Average 43 5.3  7.0 35 46 81.0 779 2083 2857 St dev 24 2.6  3.3  710 9  156  409  693

TABLE 4 Shear modulus data for example 2 Viscosity/Pa · s Time to gel Atgel Increase Shear modulus/Pa Example 1 onset/s Initial onset % Initial5 min 10 min 15 min 20 min 47  8.1 11.2 38 47 124 590 900 1009 63 12.016.7 39 42 126 503 699  894 65 15.6 20.6 32 93 186 652 913 4741 Average58 11.9 16.2 37 61 125 582 837 1050 St dev 10  3.8  4.7  4 28  1  75 120 181

As described previously when the gel solution converts from a liquid toa solid, there is a change in the measured phase angle for the gel.These results (Tables 3 & 4) demonstrate that the initial gelationincreases the modulus of the solution and that although the initialmoduli of examples 1 & 2 are different, they both increase by similarpercentages in the initial gelation (35%+/−7% for example 1 and 37%+/−4%for example 2). The data in Tables 3 & 4 that relate sample shearmodulus to time, demonstrates that the gelation process continues formany minutes after the initial gel onset. The gelation process resultingin a 62 fold increase in the viscosity of example 1 and a 17 foldincrease in example 2 after 40 minutes.

What is claimed is:
 1. A method for treatment of a wound or skin injurycomprising applying a medicament on said wound or skin injury whereinsaid medicament comprises a composition which is in sprayable form priorto application to the wound or skin injury, comprising from 0.25% to1.5% by weight of the composition of a gellan gum, and wherein theviscosity of said composition: (a) ranges from 0.1 Pa·s to 12 Pa·s priorto application to the wound or skin injury, and (b) increases onceapplied to the wound or skin injury such that an immobile gel is formed.2. A method of forming an in situ immobile gel on a wound or skin injurycomprising the step of: dispensing on the wound or skin injury aneffective amount of a composition which is in sprayable form prior toapplication to the wound or skin injury, comprises from 0.25% to 1.5% byweight of the composition of a gellan gum, and wherein the viscosity ofsaid composition: (a) ranges from 0.1 Pa·s to 12 Pa·s prior toapplication to the wound or skin injury, and (b) increases once appliedto the wound or skin injury such that an immobile gel is formed.
 3. Themethod of claim 2 wherein the dispensing step comprises spraying,painting or squirting the composition on the wound or skin injury.